The project is a collaboration with the Bill and Melinda Gates Foundation, including investigators from Stellenbosch University (SUN) and the University of Cape Town (UCT). (1) NIAID 15-I-N070: NexGen EBA radiologic and immunologic biomarkers to enhance early bactericidal activity measurements of sterilizing drug activity in tuberculosis. This study hypothesizes that drug regimens associated with higher sterilizing activity (e.g., containing rifampin or pyrazinamide) will show distinctive early cytokine and chemokine patterns and discrete, quantifiable changes on PET/CT scans in certain lesion types during the 2-week early bactericidal activity (EBA) treatment period, compared to drug regimens with poor sterilizing activity (e.g., containing isoniazid or moxifloxacin). Demonstration of such an association would provide rationale for including radiologic and immunologic analysis, alongside conventional EBA, in early phase clinical studies of novel drugs, and would also provide important new insights into the biology of human and bacterial responses to TB drugs. The primary objective is to characterize, in the context of a standard EBA study, the effect of various antituberculosis drugs on radiographic and immunologic markers as measured by PET/CT and immunologic assays, in treatment-nave subjects with pulmonary drug sensitive tuberculosis. If adding immunologic and/or radiographic markers to the standard EBA microbiologic markers improves the ability of EBA studies to predict sterilizing treatment, the EBA studies may be able to predict better which novel drugs or drug combinations will be more effective and thereby should move forward into phase 2 or 3 trials. The study initiated on December 3, 2015 and, as of August 2, 2017, has screened 256 subjects and enrolled 170 subjects. (2) NIAID 16-I-N133: Using Biomarkers to Predict TB Treatment Duration. This study hypothesizes that a combination of radiographic characteristics at baseline, the rate of change of these features at one month, and markers of residual bacterial load at the end of treatment will identify patients with tuberculosis who are cured with 4 months (16 weeks) of standard treatment. The primary objective is to demonstrate that the 18-month treatment success rate of standard treatment stopped early at week 16 (Arm C) is not inferior to standard treatment stopped at week 24 (Arm B), in participants classified as low risk for disease failure and relapse by radiographic and bacterial load markers. This is a collaborative study with funding from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership, the National Natural Science Foundation of China, the China Ministry of Science and Technology, and the NIH. Study enrollment began on 6/22/2017 across 5 sites in South Africa and, as of August 1, 2017, had screened 10 and enrolled 7. The 4 sites in Henan Province, China are awaiting final regulatory approvals and are expected to be activated soon. The study will enroll 620 participants total and is expected to complete in FY 2022.